The present invention relates to methods of treating injury from exposure to radiation or chemicals.
Hematopoietic stem cells (HSCs) are precursor cells that give rise to all blood cell types of both the myeloid and lymphoid lineages. Thus, HSC are necessary for the production of red blood cells, platelets, and lymphocytes, as well as most other blood cells. HSCs are intimately associated in vivo with discrete niches in the bone marrow, which provide molecular signals that collectively mediate HSC differentiation and self-renewal, via cell-cell contacts or short-range interactions. These niches are part of the hematopoietic inductive microenvironment, or stroma, that includes marrow cells, i.e. macrophages, fibroblasts, adipocytes and endothelial cells. The marrow cells maintain the functional integrity of the microenvironment by providing extra cellular matrix (ECM) proteins and basement membrane components that facilitate cell-cell contact. They also provide various soluble or resident cytokines needed for controlled hematopoietic cell differentiation and proliferation. The interactions between the HSC and the stroma are required to preserve the viability of the HSCs and to prevent their differentiation.
HSCs may be lost due to disease or exposure to substances that are toxic for this rapidly dividing population of cells. For example, exposure to harmful levels of radiation causes HSC death. Chemicals, including those used in cancer chemotherapy, may also kill HSCs. Patients deficient in HSCs no longer produce sufficient numbers of blood cells needed for functions ranging from oxygen transport (red blood cells), to clotting (platelets), to immunity (T cells, B cells). A complete loss of HSCs results in death in a matter of days if the patient is not treated by HSC transplantation. But even patients in which the number of HSCs is reduced but not completely lost are at grave risk of anemia, bleeding, infection, and other life-threatening conditions.
Although HSC transplantation can be used to treat conditions in which a subject has an insufficient number of HSCs, the low survival rate of the transplanted cells is a major problem. It is well documented that HSC transplanted intravenously are cleared from the circulation and visualized in the bone marrow within minutes after their transfusion. Three to five hours after HSCs transplantation, no donor cells are detected in the peripheral blood of the recipients. [Askenasy et al., Stem Cells 2002; 20:301-10.] But the vast majority of the transplanted cells are destroyed shortly after being transfused. Consequently, the colonization of the recipient's marrow is of low efficiency and only 1-5% of the transfused cells are detected in the recipient bone marrow 2-3 days post transplantation [Kerre et al., J Immunol. 2001; 167:3692-8; Jetmore et al., Blood 2002; 99:1585-93].
Several publications have demonstrated higher engraftment efficiencies of HSC when co-transplanted with mesenchymal stem cells. [Gurevitch et al., Transplantation 1999; 68:1362-8; Fan et al., Stem Cells 2001; 19:144-50.] It was also demonstrated that co-transplantation of human mesenchymal stem cells in a human-sheep engraftment model resulted in the enhancement of long-term engraftment of human HSC chimeric bone marrow in the animals. [Almeida-Porada et al., Blood 2000; 95:3620-7.] Simultaneous injection of HSC and mesenchymal stem cells can accelerate hematopoiesis. [Zhang et al., Stem Cells 2004; 22:1256-62; Liu et al., Zhonghua Xue Ye Xue Za Zhi. 2005; 26:385-8.] Mesenchymal stem cells have been used to promote engraftment of HSC in human subjects. [Koc O N, J Clin Oncol. 2000; 18:307-316; Lazarus H M, Biol Blood Marrow Transplant. 2005; 11:389-98.]. Apparently the mesenchymal stem cells contribution to hematopoietic engraftment by producing supporting cytokines that help mediate and balance the homing, self-renewal and commitment potentials of the transplanted HSCs, by rebuilding the damaged hematopoietic microenvironment needed for the homing and proliferation of the HSCs, and by inhibiting donor derived T cells, which may cause Graft vs. Host Disease (GvHD). [Charbord & Moore, Ann. N. Y. Acad. Sci 2005; 1044: 159-67; U.S. Pat. Nos. 6,010,696; 6,555,374.]
Although mesenchymal stem cells may facilitate HSC engraftment, they are not widely available in sufficient numbers for routine clinical application. Similarly, it can be difficult to provide an adequate supply of HSC, particularly HSC that are matched with the recipient and so less likely to be destroyed. Accordingly, there remains an unmet clinical need for alternatives therapies that may be used to treat subjects in which the hematopoietic system has been damaged, such as by exposure to radiation or chemicals.